protein disulfide isomerase, eukaryotic; This model represents eukaryotic protein disulfide isomerases retained in the endoplasmic reticulum (ER) and closely related forms. Some members have been assigned alternative or additional functions such as prolyl 4-hydroxylase and dolichyl-diphosphooligosaccharide-protein glycotransferase. Members of this family have at least two protein-disulfide domains, each similar to thioredoxin but with the redox-active disulfide in the motif PWCGHCK, and an ER retention signal at the extreme C-terminus (KDEL, HDEL, and similar motifs).

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 42562703    79 VLELNGDYTKRVIDGNEFVMVLGYAPWCARSAELMPRFAEAATALKEIGSSVLMAKIDGDRYSKIASELEIKGFPTLLLF 158
Cdd:TIGR01130   3 VLVLTKDNFDDFIKSHEFVLVEFYAPWCGHCKSLAPEYEKAADELKKKGPPIKLAKVDATEEKDLAQKYGVSGYPTLKIF 82

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 42562703   159 VNG--TSLTYNGGSSAEDIVIWVQKKTGAPIITLNTVDEAPRFLDKYHTFVLGLFEKFEGSEHNEFVKAAKSDDEIQFIE 236
Cdd:TIGR01130  83 RNGedSVSDYNGPRDADGIVKYMKKQSGPAVKEIETVADLEAFLADDDVVVIGFFKDLDSELNDTFLSVAEKLRDVYFFF 162

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 42562703   237 TRDSDVAKLLFPDLKSNNVFIGLVKPEAERYTVYDGSYK--MEKILEFLGSNKFPLFTKLTETNTVWVYSSPVKLQVMLF 314
Cdd:TIGR01130 163 AHSSDVAAFAKLGAFPDSVVLFKPKDEDEKFSKVDGEMDtdVSDLEKFIRAESLPLVGEFTQETAAKYFESGPLVVLYYN 242

                         250       260       270       280       290       300       310       320
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 42562703   315 SKADD--FQKLAQPLEDIARKFKSKlmFIYVDITNENLAMPFLILFGIEAGNKTVVAAFDNNLNSKYLLESDP-SPNSIE 391
Cdd:TIGR01130 243 VDESLdpFEELRNRFLEAAKKFRGK--FVNFAVADEEDFGRELEYFGLKAEKFPAVAIQDLEGNKKYPMDQEEfSSENLE 320

                         330       340       350       360       370       380       390       400
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 42562703   392 EFCSGLAHGTVSRYYRSEPVPDNENASIVTVVGKTFDGLVLNSRENVLLEVHTPWCVNCEALSKQIEKLAKHFKGFE-NL 470
Cdd:TIGR01130 321 AFVKDFLDGKLKPYLKSEPIPEDDEGPVKVLVGKNFDEIVLDETKDVLVEFYAPWCGHCKNLAPIYEELAEKYKDAEsDV 400

                         410       420       430       440       450
                  ....*....|....*....|....*....|....*....|....*....|....
gi 42562703   471 VFARIDASANEHTKLQVDDkYPIILLYKSGEKEKPLKLSTKLSAKDIAVFINEE 524
Cdd:TIGR01130 401 VIAKMDATANDVPPFEVEG-FPTIKFVPAGKKSEPVPYDGDRTLEDFSKFIAKH 453

protein disulfide isomerase, eukaryotic; This model represents eukaryotic protein disulfide isomerases retained in the endoplasmic reticulum (ER) and closely related forms. Some members have been assigned alternative or additional functions such as prolyl 4-hydroxylase and dolichyl-diphosphooligosaccharide-protein glycotransferase. Members of this family have at least two protein-disulfide domains, each similar to thioredoxin but with the redox-active disulfide in the motif PWCGHCK, and an ER retention signal at the extreme C-terminus (KDEL, HDEL, and similar motifs).

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 42562703    79 VLELNGDYTKRVIDGNEFVMVLGYAPWCARSAELMPRFAEAATALKEIGSSVLMAKIDGDRYSKIASELEIKGFPTLLLF 158
Cdd:TIGR01130   3 VLVLTKDNFDDFIKSHEFVLVEFYAPWCGHCKSLAPEYEKAADELKKKGPPIKLAKVDATEEKDLAQKYGVSGYPTLKIF 82

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 42562703   159 VNG--TSLTYNGGSSAEDIVIWVQKKTGAPIITLNTVDEAPRFLDKYHTFVLGLFEKFEGSEHNEFVKAAKSDDEIQFIE 236
Cdd:TIGR01130  83 RNGedSVSDYNGPRDADGIVKYMKKQSGPAVKEIETVADLEAFLADDDVVVIGFFKDLDSELNDTFLSVAEKLRDVYFFF 162

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 42562703   237 TRDSDVAKLLFPDLKSNNVFIGLVKPEAERYTVYDGSYK--MEKILEFLGSNKFPLFTKLTETNTVWVYSSPVKLQVMLF 314
Cdd:TIGR01130 163 AHSSDVAAFAKLGAFPDSVVLFKPKDEDEKFSKVDGEMDtdVSDLEKFIRAESLPLVGEFTQETAAKYFESGPLVVLYYN 242

                         250       260       270       280       290       300       310       320
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 42562703   315 SKADD--FQKLAQPLEDIARKFKSKlmFIYVDITNENLAMPFLILFGIEAGNKTVVAAFDNNLNSKYLLESDP-SPNSIE 391
Cdd:TIGR01130 243 VDESLdpFEELRNRFLEAAKKFRGK--FVNFAVADEEDFGRELEYFGLKAEKFPAVAIQDLEGNKKYPMDQEEfSSENLE 320

                         330       340       350       360       370       380       390       400
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 42562703   392 EFCSGLAHGTVSRYYRSEPVPDNENASIVTVVGKTFDGLVLNSRENVLLEVHTPWCVNCEALSKQIEKLAKHFKGFE-NL 470
Cdd:TIGR01130 321 AFVKDFLDGKLKPYLKSEPIPEDDEGPVKVLVGKNFDEIVLDETKDVLVEFYAPWCGHCKNLAPIYEELAEKYKDAEsDV 400

                         410       420       430       440       450
                  ....*....|....*....|....*....|....*....|....*....|....
gi 42562703   471 VFARIDASANEHTKLQVDDkYPIILLYKSGEKEKPLKLSTKLSAKDIAVFINEE 524
Cdd:TIGR01130 401 VIAKMDATANDVPPFEVEG-FPTIKFVPAGKKSEPVPYDGDRTLEDFSKFIAKH 453

PDIa family, C-terminal TRX domain (a') subfamily; composed of the C-terminal redox active a' domains of PDI, ERp72, ERp57 (or ERp60) and EFP1. PDI, ERp72 and ERp57 are endoplasmic reticulum (ER)-resident eukaryotic proteins involved in oxidative protein folding. They are oxidases, catalyzing the formation of disulfide bonds of newly synthesized polypeptides in the ER. They also exhibit reductase activity in acting as isomerases to correct any non-native disulfide bonds, as well as chaperone activity to prevent protein aggregation and facilitate the folding of newly synthesized proteins. PDI and ERp57 have the abb'a' domain structure (where a and a' are redox active TRX domains while b and b' are redox inactive TRX-like domains). PDI also contains an acidic region (c domain) after the a' domain that is absent in ERp57. ERp72 has an additional a domain at the N-terminus (a"abb'a' domain structure). ERp57 interacts with the lectin chaperones, calnexin and calreticulin, and specifically promotes the oxidative folding of glycoproteins, while PDI shows a wider substrate specificity. ERp72 associates with several ER chaperones and folding factors to form complexes in the ER that bind nascent proteins. EFP1 is a binding partner protein of thyroid oxidase, which is responsible for the generation of hydrogen peroxide, a crucial substrate of thyroperoxidase, which functions to iodinate thyroglobulin and synthesize thyroid hormones.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 42562703 418 SIVTVVGKTFDGLVLNSRENVLLEVHTPWCVNCEALSKQIEKLAKHFKGFENLVFARIDASANEHTKLQVDDKYPIILLY 497
Cdd:cd02995   1 PVKVVVGKNFDEVVLDSDKDVLVEFYAPWCGHCKALAPIYEELAEKLKGDDNVVIAKMDATANDVPSEFVVDGFPTILFF 80

                        90       100
                ....*....|....*....|....
gi 42562703 498 KSGEKEKPLKLSTKLSAKDIAVFI 521
Cdd:cd02995  81 PAGDKSNPIKYEGDRTLEDLIKFI 104

Thioredoxin-like domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 42562703   211 FEKFEGSEHNEFVKAAKS-DDEIQFIETRDSDVAKLLfpDLKSNNVFigLVKPEAERYTVYDG-SYKMEKILEFLGSNKF 288
Cdd:pfam13848   1 FEDKDSPLYEIFRKAAKElKGDVRFGITFSKEVADKY--NIKEPAIL--LFRKFDEETVHYPGdSINFEDLKKFIQKNCL 76

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 42562703   289 PLFTKLTETNTVWVYSSPVKLQVMLFSKADD--FQKLAQPLEDIARKFKSKLMFIYVDITNENLampFLILFGIEAGNKT 366
Cdd:pfam13848  77 PLVREFTPENAEELFEEGIPPLLLLFLKKDDesTEEFKKALEKVAKKFRGKINFALVDAKSFGR---PLEYFGLSESDLP 153

                         170       180
                  ....*....|....*....|....*....
gi 42562703   367 VVAAFDN-NLNSKYLLESDPSPNSIEEFC 394
Cdd:pfam13848 154 VIVIVDSfSHMYKYFPSDEFSPESLKEFI 182

protein disulfide isomerase, eukaryotic; This model represents eukaryotic protein disulfide isomerases retained in the endoplasmic reticulum (ER) and closely related forms. Some members have been assigned alternative or additional functions such as prolyl 4-hydroxylase and dolichyl-diphosphooligosaccharide-protein glycotransferase. Members of this family have at least two protein-disulfide domains, each similar to thioredoxin but with the redox-active disulfide in the motif PWCGHCK, and an ER retention signal at the extreme C-terminus (KDEL, HDEL, and similar motifs).

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 42562703    79 VLELNGDYTKRVIDGNEFVMVLGYAPWCARSAELMPRFAEAATALKEIGSSVLMAKIDGDRYSKIASELEIKGFPTLLLF 158
Cdd:TIGR01130   3 VLVLTKDNFDDFIKSHEFVLVEFYAPWCGHCKSLAPEYEKAADELKKKGPPIKLAKVDATEEKDLAQKYGVSGYPTLKIF 82

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 42562703   159 VNG--TSLTYNGGSSAEDIVIWVQKKTGAPIITLNTVDEAPRFLDKYHTFVLGLFEKFEGSEHNEFVKAAKSDDEIQFIE 236
Cdd:TIGR01130  83 RNGedSVSDYNGPRDADGIVKYMKKQSGPAVKEIETVADLEAFLADDDVVVIGFFKDLDSELNDTFLSVAEKLRDVYFFF 162

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 42562703   237 TRDSDVAKLLFPDLKSNNVFIGLVKPEAERYTVYDGSYK--MEKILEFLGSNKFPLFTKLTETNTVWVYSSPVKLQVMLF 314
Cdd:TIGR01130 163 AHSSDVAAFAKLGAFPDSVVLFKPKDEDEKFSKVDGEMDtdVSDLEKFIRAESLPLVGEFTQETAAKYFESGPLVVLYYN 242

                         250       260       270       280       290       300       310       320
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 42562703   315 SKADD--FQKLAQPLEDIARKFKSKlmFIYVDITNENLAMPFLILFGIEAGNKTVVAAFDNNLNSKYLLESDP-SPNSIE 391
Cdd:TIGR01130 243 VDESLdpFEELRNRFLEAAKKFRGK--FVNFAVADEEDFGRELEYFGLKAEKFPAVAIQDLEGNKKYPMDQEEfSSENLE 320

                         330       340       350       360       370       380       390       400
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 42562703   392 EFCSGLAHGTVSRYYRSEPVPDNENASIVTVVGKTFDGLVLNSRENVLLEVHTPWCVNCEALSKQIEKLAKHFKGFE-NL 470
Cdd:TIGR01130 321 AFVKDFLDGKLKPYLKSEPIPEDDEGPVKVLVGKNFDEIVLDETKDVLVEFYAPWCGHCKNLAPIYEELAEKYKDAEsDV 400

                         410       420       430       440       450
                  ....*....|....*....|....*....|....*....|....*....|....
gi 42562703   471 VFARIDASANEHTKLQVDDkYPIILLYKSGEKEKPLKLSTKLSAKDIAVFINEE 524
Cdd:TIGR01130 401 VIAKMDATANDVPPFEVEG-FPTIKFVPAGKKSEPVPYDGDRTLEDFSKFIAKH 453

PDIa family, C-terminal TRX domain (a') subfamily; composed of the C-terminal redox active a' domains of PDI, ERp72, ERp57 (or ERp60) and EFP1. PDI, ERp72 and ERp57 are endoplasmic reticulum (ER)-resident eukaryotic proteins involved in oxidative protein folding. They are oxidases, catalyzing the formation of disulfide bonds of newly synthesized polypeptides in the ER. They also exhibit reductase activity in acting as isomerases to correct any non-native disulfide bonds, as well as chaperone activity to prevent protein aggregation and facilitate the folding of newly synthesized proteins. PDI and ERp57 have the abb'a' domain structure (where a and a' are redox active TRX domains while b and b' are redox inactive TRX-like domains). PDI also contains an acidic region (c domain) after the a' domain that is absent in ERp57. ERp72 has an additional a domain at the N-terminus (a"abb'a' domain structure). ERp57 interacts with the lectin chaperones, calnexin and calreticulin, and specifically promotes the oxidative folding of glycoproteins, while PDI shows a wider substrate specificity. ERp72 associates with several ER chaperones and folding factors to form complexes in the ER that bind nascent proteins. EFP1 is a binding partner protein of thyroid oxidase, which is responsible for the generation of hydrogen peroxide, a crucial substrate of thyroperoxidase, which functions to iodinate thyroglobulin and synthesize thyroid hormones.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 42562703 418 SIVTVVGKTFDGLVLNSRENVLLEVHTPWCVNCEALSKQIEKLAKHFKGFENLVFARIDASANEHTKLQVDDKYPIILLY 497
Cdd:cd02995   1 PVKVVVGKNFDEVVLDSDKDVLVEFYAPWCGHCKALAPIYEELAEKLKGDDNVVIAKMDATANDVPSEFVVDGFPTILFF 80

                        90       100
                ....*....|....*....|....
gi 42562703 498 KSGEKEKPLKLSTKLSAKDIAVFI 521
Cdd:cd02995  81 PAGDKSNPIKYEGDRTLEDLIKFI 104

PDIa family, TMX3 subfamily; composed of eukaryotic proteins similar to human TMX3, a TRX related transmembrane protein containing one redox active TRX domain at the N-terminus and a classical ER retrieval sequence for type I transmembrane proteins at the C-terminus. The TMX3 transcript is found in a variety of tissues with the highest levels detected in skeletal muscle and the heart. In vitro, TMX3 showed oxidase activity albeit slightly lower than that of protein disulfide isomerase.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 42562703  79 VLELNGDYTKRVIDGNEFVMVlgYAPWCARSAELMPRFAEAATALKEIGSSVLMAKIDGDRYSKIASELEIKGFPTLLLF 158
Cdd:cd03000   2 VLDLDDSFKDVRKEDIWLVDF--YAPWCGHCKKLEPVWNEVGAELKSSGSPVRVGKLDATAYSSIASEFGVRGYPTIKLL 79

                        90
                ....*....|....*...
gi 42562703 159 VNGTSLTYNGGSSAEDIV 176
Cdd:cd03000  80 KGDLAYNYRGPRTKDDIV 97

Protein Disulfide Isomerase (PDIa) family, redox active TRX domains; composed of eukaryotic proteins involved in oxidative protein folding in the endoplasmic reticulum (ER) by acting as catalysts and folding assistants. Members of this family include PDI and PDI-related proteins like ERp72, ERp57 (or ERp60), ERp44, P5, PDIR, ERp46 and the transmembrane PDIs. PDI, ERp57, ERp72, P5, PDIR and ERp46 are all oxidases, catalyzing the formation of disulfide bonds of newly synthesized polypeptides in the ER. They also exhibit reductase activity in acting as isomerases to correct any non-native disulfide bonds, as well as chaperone activity to prevent protein aggregation and facilitate the folding of newly synthesized proteins. These proteins usually contain multiple copies of a redox active TRX (a) domain containing a CXXC motif, and may also contain one or more redox inactive TRX-like (b) domains. Only one a domain is required for the oxidase function but multiple copies are necessary for the isomerase function. The different types of PDIs may show different substrate specificities and tissue-specific expression, or may be induced by stress. PDIs are in their reduced form at steady state and are oxidized to the active form by Ero1, which is localized in the ER through ERp44. Some members of this family also contain a DnaJ domain in addition to the redox active a domains; examples are ERdj5 and Pfj2. Also included in the family is the redox inactive N-terminal TRX-like domain of ERp29.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 42562703 420 VTVVGKTFDGLVLNSrENVLLEVHTPWCVNCEALSKQIEKLAKHFKGFENLVFARIDASAN-EHTKLQVDDKYPIILLYK 498
Cdd:cd02961   1 VELTDDNFDELVKDS-KDVLVEFYAPWCGHCKALAPEYEKLAKELKGDGKVVVAKVDCTANnDLCSEYGVRGYPTIKLFP 79

                        90       100
                ....*....|....*....|...
gi 42562703 499 SGEKeKPLKLSTKLSAKDIAVFI 521
Cdd:cd02961  80 NGSK-EPVKYEGPRTLESLVEFI 101

Protein Disulfide Isomerase (PDIb) family, redox inactive TRX-like domain b; composed of eukaryotic proteins involved in oxidative protein folding in the endoplasmic reticulum (ER) by acting as catalysts and folding assistants. Members of this family include PDI, calsequestrin and other PDI-related proteins like ERp72, ERp57, ERp44 and PDIR. PDI, ERp57 (or ERp60), ERp72 and PDIR are all oxidases, catalyzing the formation of disulfide bonds of newly synthesized polypeptides in the ER. They also exhibit reductase activity in acting as isomerases to correct any non-native disulfide bonds, as well as chaperone activity to prevent protein aggregation and facilitate the folding of newly synthesized proteins. These proteins contain multiple copies of a redox active TRX (a) domain containing a CXXC motif, and one or more redox inactive TRX-like (b) domains. The molecular structure of PDI is abb'a'. Also included in this family is the PDI-related protein ERp27, which contains only redox-inactive TRX-like (b and b') domains. The redox inactive b domains are implicated in substrate recognition.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 42562703 187 IITLNTVDEAPRFLDKYHTFVLGLFEKFEGSEHNEFVKAAKS-DDEIQFIETRDSDVAKLlfpdLKSNNVFIGLVKPEAE 265
Cdd:cd02981   1 VKELTSKEELEKFLDKDDVVVVGFFKDEESEEYKTFEKVAESlRDDYGFGHTSDKEVAKK----LKVKPGSVVLFKPFEE 76

                        90       100
                ....*....|....*....|.
gi 42562703 266 RYTVYDGSYKMEKILEFLGSN 286
Cdd:cd02981  77 EPVEYDGEFTEESLVEFIKDN 97

PDIa family, endoplasmic reticulum protein 38 (ERp38) subfamily; composed of proteins similar to the P5-like protein first isolated from alfalfa, which contains two redox active TRX (a) domains at the N-terminus, like human P5, and a C-terminal domain with homology to the C-terminal domain of ERp29, unlike human P5. The cDNA clone of this protein (named G1) was isolated from an alfalfa cDNA library by screening with human protein disulfide isomerase (PDI) cDNA. The G1 protein is constitutively expressed in all major organs of the plant and its expression is induced by treatment with tunicamycin, indicating that it may be a glucose-regulated protein. The G1 homolog in the eukaryotic social amoeba Dictyostelium discoideum is also described as a P5-like protein, which is located in the endoplasmic reticulum (ER) despite the absence of an ER-retrieval signal. G1 homologs from Aspergillus niger and Neurospora crassa have also been characterized, and are named TIGA and ERp38, respectively. Also included in the alignment is an atypical PDI from Leishmania donovani containing a single a domain, and the C-terminal a domain of a P5-like protein from Entamoeba histolytica.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 42562703  79 VLELNGD-YTKRVIDGNEFVMVLGYAPWCARSAELMPRFAEAATALKEiGSSVLMAKIDGD-RYSKIASELEIKGFPTLL 156
Cdd:cd02998   2 VVELTDSnFDKVVGDDKKDVLVEFYAPWCGHCKNLAPEYEKLAAVFAN-EDDVVIAKVDADeANKDLAKKYGVSGFPTLK 80

                        90       100
                ....*....|....*....|....*
gi 42562703 157 LFVNGTS--LTYNGGSSAEDIVIWV 179
Cdd:cd02998  81 FFPKGSTepVKYEGGRDLEDLVKFV 105

PDIa family, endoplasmic reticulum protein 44 (ERp44) subfamily; ERp44 is an ER-resident protein, induced during stress, involved in thiol-mediated ER retention. It contains an N-terminal TRX domain, similar to that of PDIa, with a CXFS motif followed by two redox inactive TRX-like domains, homologous to the b and b' domains of PDI. The CXFS motif in the N-terminal domain allows ERp44 to form stable reversible mixed disulfides with its substrates. Through this activity, ERp44 mediates the ER localization of Ero1alpha, a protein that oxidizes protein disulfide isomerases into their active form. ERp44 also prevents the secretion of unassembled cargo protein with unpaired cysteines. It also modulates the activity of inositol 1,4,5-triphosphate type I receptor (IP3R1), an intracellular channel protein that mediates calcium release from the ER to the cytosol.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 42562703  90 VIDGNEFVMVLGYAPWCARSAELMPRFAEAATALKEI---GSSVLMAKIDGDRYSKIASELEIKGFPTLLLFVNGTSLT- 165
Cdd:cd02996  14 ILQSAELVLVNFYADWCRFSQMLHPIFEEAAAKIKEEfpdAGKVVWGKVDCDKESDIADRYRINKYPTLKLFRNGMMMKr 93

                        90
                ....*....|....*
gi 42562703 166 -YNGGSSAEDIVIWV 179
Cdd:cd02996  94 eYRGQRSVEALAEFV 108

PDIa family, C-terminal TRX domain (a') subfamily; composed of the C-terminal redox active a' domains of PDI, ERp72, ERp57 (or ERp60) and EFP1. PDI, ERp72 and ERp57 are endoplasmic reticulum (ER)-resident eukaryotic proteins involved in oxidative protein folding. They are oxidases, catalyzing the formation of disulfide bonds of newly synthesized polypeptides in the ER. They also exhibit reductase activity in acting as isomerases to correct any non-native disulfide bonds, as well as chaperone activity to prevent protein aggregation and facilitate the folding of newly synthesized proteins. PDI and ERp57 have the abb'a' domain structure (where a and a' are redox active TRX domains while b and b' are redox inactive TRX-like domains). PDI also contains an acidic region (c domain) after the a' domain that is absent in ERp57. ERp72 has an additional a domain at the N-terminus (a"abb'a' domain structure). ERp57 interacts with the lectin chaperones, calnexin and calreticulin, and specifically promotes the oxidative folding of glycoproteins, while PDI shows a wider substrate specificity. ERp72 associates with several ER chaperones and folding factors to form complexes in the ER that bind nascent proteins. EFP1 is a binding partner protein of thyroid oxidase, which is responsible for the generation of hydrogen peroxide, a crucial substrate of thyroperoxidase, which functions to iodinate thyroglobulin and synthesize thyroid hormones.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 42562703  85 DYTKRVIDGNEFVMVLGYAPWCARSAELMPRFAEAATALKEiGSSVLMAKIDGDRySKIASELEIKGFPTLLLFVNG--- 161
Cdd:cd02995   9 NFDEVVLDSDKDVLVEFYAPWCGHCKALAPIYEELAEKLKG-DDNVVIAKMDATA-NDVPSEFVVDGFPTILFFPAGdks 86

                        90
                ....*....|....*...
gi 42562703 162 TSLTYNGGSSAEDIVIWV 179
Cdd:cd02995  87 NPIKYEGDRTLEDLIKFI 104

PDIa family, endoplasmic reticulum protein 38 (ERp38) subfamily; composed of proteins similar to the P5-like protein first isolated from alfalfa, which contains two redox active TRX (a) domains at the N-terminus, like human P5, and a C-terminal domain with homology to the C-terminal domain of ERp29, unlike human P5. The cDNA clone of this protein (named G1) was isolated from an alfalfa cDNA library by screening with human protein disulfide isomerase (PDI) cDNA. The G1 protein is constitutively expressed in all major organs of the plant and its expression is induced by treatment with tunicamycin, indicating that it may be a glucose-regulated protein. The G1 homolog in the eukaryotic social amoeba Dictyostelium discoideum is also described as a P5-like protein, which is located in the endoplasmic reticulum (ER) despite the absence of an ER-retrieval signal. G1 homologs from Aspergillus niger and Neurospora crassa have also been characterized, and are named TIGA and ERp38, respectively. Also included in the alignment is an atypical PDI from Leishmania donovani containing a single a domain, and the C-terminal a domain of a P5-like protein from Entamoeba histolytica.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 42562703 418 SIVTVVGKTFDGLVLNSRENVLLEVHTPWCVNCEALSKQIEKLAKHFKGFENLVFARIDASANEH---TKLQVDDkYPII 494
Cdd:cd02998   1 NVVELTDSNFDKVVGDDKKDVLVEFYAPWCGHCKNLAPEYEKLAAVFANEDDVVIAKVDADEANKdlaKKYGVSG-FPTL 79

                        90       100
                ....*....|....*....|....*..
gi 42562703 495 LLYKSGEKEkPLKLSTKLSAKDIAVFI 521
Cdd:cd02998  80 KFFPKGSTE-PVKYEGGRDLEDLVKFV 105

PDI family, MPD1-like subfamily; composed of eukaryotic proteins similar to Saccharomyces cerevisiae MPD1 protein, which contains a single redox active TRX domain located at the N-terminus, and an ER retention signal at the C-terminus indicative of an ER-resident protein. MPD1 has been shown to suppress the maturation defect of carboxypeptidase Y caused by deletion of the yeast PDI1 gene. Other characterized members of this subfamily include the Aspergillus niger prpA protein and Giardia PDI-1. PrpA is non-essential to strain viability, however, its transcript level is induced by heterologous protein expression suggesting a possible role in oxidative protein folding during high protein production. Giardia PDI-1 has the ability to refold scrambled RNase and exhibits transglutaminase activity.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 42562703  79 VLELNGDYTKRVIDGNEFV-MVLGYAPWCARSAELMPRFAEAAtalKEIGSSVLMAKIDGDRYS--KIASELEIKGFPTL 155
Cdd:cd03002   2 VYELTPKNFDKVVHNTNYTtLVEFYAPWCGHCKNLKPEYAKAA---KELDGLVQVAAVDCDEDKnkPLCGKYGVQGFPTL 78

                        90       100
                ....*....|....*....|....*..
gi 42562703 156 LLF------VNGTSLTYNGGSSAEDIV 176
Cdd:cd03002  79 KVFrppkkaSKHAVEDYNGERSAKAIV 105

thioredoxin; Several proteins, such as protein disulfide isomerase, have two or more copies of a domain closely related to thioredoxin. This model is designed to recognize authentic thioredoxin, a small protein that should be hit exactly once by this model. Any protein that hits once with a score greater than the second (per domain) trusted cutoff may be taken as thioredoxin. [Energy metabolism, Electron transport]

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 42562703    90 VIDGNEFVMVLGYAPWCARSAELMPRFAEAAtalKEIGSSVLMAKIDGDRYSKIASELEIKGFPTLLLFVNG 161
Cdd:TIGR01068  10 IASSDKPVLVDFWAPWCGPCKMIAPILEELA---KEYEGKVKFVKLNVDENPDIAAKYGIRSIPTLLLFKNG 78

TRX family; composed of two groups: Group I, which includes proteins that exclusively encode a TRX domain; and Group II, which are composed of fusion proteins of TRX and additional domains. Group I TRX is a small ancient protein that alter the redox state of target proteins via the reversible oxidation of an active site dithiol, present in a CXXC motif, partially exposed at the protein's surface. TRX reduces protein disulfide bonds, resulting in a disulfide bond at its active site. Oxidized TRX is converted to the active form by TRX reductase, using reducing equivalents derived from either NADPH or ferredoxins. By altering their redox state, TRX regulates the functions of at least 30 target proteins, some of which are enzymes and transcription factors. It also plays an important role in the defense against oxidative stress by directly reducing hydrogen peroxide and certain radicals, and by serving as a reductant for peroxiredoxins. At least two major types of functional TRXs have been reported in most organisms; in eukaryotes, they are located in the cytoplasm and the mitochondria. Higher plants contain more types (at least 20 TRX genes have been detected in the genome of Arabidopsis thaliana), two of which (types f amd m) are located in the same compartment, the chloroplast. Also included in the alignment are TRX-like domains which show sequence homology to TRX but do not contain the redox active CXXC motif. Group II proteins, in addition to either a redox active TRX or a TRX-like domain, also contain additional domains, which may or may not possess homology to known proteins.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 42562703  88 KRVIDGNEFVMVLGYAPWCARSAELMPRFAEAATAlkeiGSSVLMAKIDGDRYSKIASELEIKGFPTLLLFVNG 161
Cdd:cd02947   4 EELIKSAKPVVVDFWAPWCGPCKAIAPVLEELAEE----YPKVKFVKVDVDENPELAEEYGVRSIPTFLFFKNG 73

disulphide isomerase; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 42562703   66 QSEAETVSKAQRIVLELNGDYTKRVIDGNEFVMVLGYAPWCARSAELMPRFAEAATALKEIGsSVLMAKIDGDRYSKIAS 145
Cdd:PTZ00102 347 KSEPIPEEQDGPVKVVVGNTFEEIVFKSDKDVLLEIYAPWCGHCKNLEPVYNELGEKYKDND-SIIVAKMNGTANETPLE 425

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|...
gi 42562703  146 ELEIKGFPTLLLFVNG--TSLTYNGGSSAEDIVIWVQKKTGAP 186
Cdd:PTZ00102 426 EFSWSAFPTILFVKAGerTPIPYEGERTVEGFKEFVNKHATNP 468

PDIa family, P5 subfamily; composed of eukaryotic proteins similar to human P5, a PDI-related protein with a domain structure of aa'b (where a and a' are redox active TRX domains and b is a redox inactive TRX-like domain). Like PDI, P5 is located in the endoplasmic reticulum (ER) and displays both isomerase and chaperone activities, which are independent of each other. Compared to PDI, the isomerase and chaperone activities of P5 are lower. The first cysteine in the CXXC motif of both redox active domains in P5 is necessary for isomerase activity. The P5 gene was first isolated as an amplified gene from a hydroxyurea-resistant hamster cell line. The zebrafish P5 homolog has been implicated to play a critical role in establishing left/right asymmetries in the embryonic midline. Some members of this subfamily are P5-like proteins containing only one redox active TRX domain.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 42562703 426 TFDGLVLNSRENVLLEVHTPWCVNCEALSKQIEKLAKHFKGFENLvfARIDASANEHTKLQVDDK-YPIILLYKSGeKEK 504
Cdd:cd03001   9 NFDKKVLNSDDVWLVEFYAPWCGHCKNLAPEWKKAAKALKGIVKV--GAVDADVHQSLAQQYGVRgFPTIKVFGAG-KNS 85

                        90
                ....*....|....
gi 42562703 505 PLKLSTKLSAKDIA 518
Cdd:cd03001  86 PQDYQGGRTAKAIV 99

PDIa family, C-terminal ERdj5 subfamily; ERdj5, also known as JPDI and macrothioredoxin, is a protein containing an N-terminal DnaJ domain and four redox active TRX domains. This subfamily is composed of the three TRX domains located at the C-terminal half of the protein. ERdj5 is a ubiquitous protein localized in the endoplasmic reticulum (ER) and is abundant in secretory cells. It's transcription is induced during ER stress. It interacts with BiP through its DnaJ domain in an ATP-dependent manner. BiP, an ER-resident member of the Hsp70 chaperone family, functions in ER-associated degradation and protein translocation. Also included in the alignment is the single complete TRX domain of an uncharacterized protein from Tetraodon nigroviridis, which also contains a DnaJ domain at its N-terminus.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 42562703 418 SIVTVVGKTFDGLVLNSRENVLLEVHTPWCVNCEALSKQIEKLAKHFKGfeNLVFARIDASANEHTKLQVD-DKYPIILL 496
Cdd:cd03004   2 SVITLTPEDFPELVLNRKEPWLVDFYAPWCGPCQALLPELRKAARALKG--KVKVGSVDCQKYESLCQQANiRAYPTIRL 79

                ....*.
gi 42562703 497 YKSGEK 502
Cdd:cd03004  80 YPGNAS 85

ybbN protein family; ybbN is a hypothetical protein containing a redox-inactive TRX-like domain. Its gene has been sequenced from several gammaproteobacteria and actinobacteria.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 42562703  97 VMVLGYAPWCARSAELMPRFAEAATalkEIGSSVLMAKIDGDRYSKIASELEIKGFPTLLLFVNGTSLT-YNGGSSAEDI 175
Cdd:cd02956  15 VVVDFWAPRSPPSKELLPLLERLAE---EYQGQFVLAKVNCDAQPQIAQQFGVQALPTVYLFAAGQPVDgFQGAQPEEQL 91

                ....
gi 42562703 176 VIWV 179
Cdd:cd02956  92 RQML 95

TRX family; composed of two groups: Group I, which includes proteins that exclusively encode a TRX domain; and Group II, which are composed of fusion proteins of TRX and additional domains. Group I TRX is a small ancient protein that alter the redox state of target proteins via the reversible oxidation of an active site dithiol, present in a CXXC motif, partially exposed at the protein's surface. TRX reduces protein disulfide bonds, resulting in a disulfide bond at its active site. Oxidized TRX is converted to the active form by TRX reductase, using reducing equivalents derived from either NADPH or ferredoxins. By altering their redox state, TRX regulates the functions of at least 30 target proteins, some of which are enzymes and transcription factors. It also plays an important role in the defense against oxidative stress by directly reducing hydrogen peroxide and certain radicals, and by serving as a reductant for peroxiredoxins. At least two major types of functional TRXs have been reported in most organisms; in eukaryotes, they are located in the cytoplasm and the mitochondria. Higher plants contain more types (at least 20 TRX genes have been detected in the genome of Arabidopsis thaliana), two of which (types f amd m) are located in the same compartment, the chloroplast. Also included in the alignment are TRX-like domains which show sequence homology to TRX but do not contain the redox active CXXC motif. Group II proteins, in addition to either a redox active TRX or a TRX-like domain, also contain additional domains, which may or may not possess homology to known proteins.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 42562703 425 KTFDGLVLNSReNVLLEVHTPWCVNCEALSKQIEKLAKHFKgfeNLVFARIDASANEhtklQVDDKY-----PIILLYKS 499
Cdd:cd02947   1 EEFEELIKSAK-PVVVDFWAPWCGPCKAIAPVLEELAEEYP---KVKFVKVDVDENP----ELAEEYgvrsiPTFLFFKN 72

                ...
gi 42562703 500 GEK 502
Cdd:cd02947  73 GKE 75

5'-adenylylsulfate reductase

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 42562703   98 MVLGYAPWCARSAELMPRFAEAATALkeIGSSVLMAKI--DGDRYSKIASELEIKGFPTLLLFVNGTSLTYNGGSSAEDI 175
Cdd:PLN02309 369 LVVLYAPWCPFCQAMEASYEELAEKL--AGSGVKVAKFraDGDQKEFAKQELQLGSFPTILLFPKNSSRPIKYPSEKRDV 446

                 ....*...
gi 42562703  176 ---VIWVQ 180
Cdd:PLN02309 447 dslLSFVN 454

TRX domain, PICOT (for PKC-interacting cousin of TRX) subfamily; PICOT is a protein that interacts with protein kinase C (PKC) theta, a calcium independent PKC isoform selectively expressed in skeletal muscle and T lymphocytes. PICOT contains an N-terminal TRX-like domain, which does not contain the catalytic CXXC motif, followed by one to three glutaredoxin domains. The TRX-like domain is required for interaction with PKC theta. PICOT inhibits the activation of c-Jun N-terminal kinase and the transcription factors, AP-1 and NF-kB, induced by PKC theta or T-cell activating stimuli.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 42562703  92 DGNEFVMVLGYAPWCARSAELMPRFAEAAtalKEIGSSVLMAKIDGDRYSKIASELEIKGFPTLLLFVNGTSLTYNGGSS 171
Cdd:cd02984  12 DASKLLVLHFWAPWAEPCKQMNQVFEELA---KEAFPSVLFLSIEAEELPEISEKFEITAVPTFVFFRNGTIVDRVSGAD 88

                ....*
gi 42562703 172 AEDIV 176
Cdd:cd02984  89 PKELA 93

PDIa family, N-terminal EFP1 subfamily; EFP1 is a binding partner protein of thyroid oxidase (ThOX), also called Duox. ThOX proteins are responsible for the generation of hydrogen peroxide, a crucial substrate of thyroperoxidase, which functions to iodinate thyroglobulin and synthesize thyroid hormones. EFP1 was isolated through a yeast two-hybrid method using the EF-hand fragment of dog Duox1 as a bait. It could be one of the partners in the assembly of a multiprotein complex constituting the thyroid hydrogen peroxide generating system. EFP1 contains two TRX domains related to the redox active TRX domains of protein disulfide isomerase (PDI). This subfamily is composed of the N-terminal TRX domain of EFP1, which contains a CXXS sequence in place of the typical CXXC motif, similar to ERp44. The CXXS motif allows the formation of stable mixed disulfides, crucial for the ER-retention function of ERp44.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 42562703  85 DYTKRVIDGNEFVMVLGYAPWCARSAELMPRFAEAAtalKEIGSSVLMAKID-GDRYSKIASELEIKGFPTLLLFVNG-T 162
Cdd:cd03006  20 DYAEELRTDAEVSLVMYYAPWDAQSQAARQEFEQVA---QKLSDQVLFVAINcWWPQGKCRKQKHFFYFPVIHLYYRSrG 96

                        90
                ....*....|....*..
gi 42562703 163 SLTYNGGSSAEDIVIWV 179
Cdd:cd03006  97 PIEYKGPMRAPYMEKFV 113

PDI family, MPD1-like subfamily; composed of eukaryotic proteins similar to Saccharomyces cerevisiae MPD1 protein, which contains a single redox active TRX domain located at the N-terminus, and an ER retention signal at the C-terminus indicative of an ER-resident protein. MPD1 has been shown to suppress the maturation defect of carboxypeptidase Y caused by deletion of the yeast PDI1 gene. Other characterized members of this subfamily include the Aspergillus niger prpA protein and Giardia PDI-1. PrpA is non-essential to strain viability, however, its transcript level is induced by heterologous protein expression suggesting a possible role in oxidative protein folding during high protein production. Giardia PDI-1 has the ability to refold scrambled RNase and exhibits transglutaminase activity.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 42562703 419 IVTVVGKTFDGLVLNSRENVLLEVHTPWCVNCEALSKQIEKLAKHFKGFENLVFARIDASAN 480
Cdd:cd03002   2 VYELTPKNFDKVVHNTNYTTLVEFYAPWCGHCKNLKPEYAKAAKELDGLVQVAAVDCDEDKN 63